VH replacement in mice and humans.

Heavy chain variable segment (V(H)) replacement refers to recombination activating gene (RAG) product-mediated secondary recombination between a previously rearranged V(H) gene and an upstream unrearranged V(H) gene. V(H) replacement was first observed in mouse pre-B cell lines and later demonstrated in knock-in mouse models carrying immunoglobulin heavy chain (IgH) genes encoding self-reactive or mono-specific antibodies or non-functional IgH rearrangements on both IgH alleles. Despite these findings, it is still difficult to find V(H) replacement intermediates during normal murine B cell development. In humans, ongoing V(H) replacement was found in a clonal B lineage EU12 cell line and in human bone marrow immature B cells. The identification of potential V(H) replacement products also suggested a potential contribution of V(H) replacement to the antibody repertoire. Here, I review the evidence for whether V(H) replacement genuinely offers an in vivo RAG-mediated recombinatorial mechanism to alter preformed IgH genes in mice and humans.